Processes for the production of chinazoline alkaloids

ABSTRACT

Processes for the production of a compound of the following formula (I)  
                 
 
by converting a compound of formula (II) with 2-pyrrolidone used in excess relative to compound (II) and processes for the production of a compound of formula (III).  
                 
The latter process includes preparing compound (I); a reduction reaction which yields compound (III) in salt form; and liberating compound (III) from the salt.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application of InternationalApplication No. PCT/EP2004/000485, filed on Jan. 22, 2004, which claimspriority of German application number 103 04 141.9, filed on Feb. 3,2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention refers to processes for the production ofchinazoline alkaloids of the following formulas (I) and (III).

2. Description of the Prior Art

Compound (III) is 1,2,3,9-tetrahydropyrrolo[2,1-b]chinazoline. Thiscompound is also known under the trivial name of deoxypeganine andoccurs in plants of the Zygophyllaceae family. Because of itspharmacological properties, deoxypeganine is regarded as a member of thegroup of reversibly active cholinesterase inhibitors.

Apart from this, it also acts as a monoamine oxidase inhibitor.Deoxypeganine is taken into consideration as a medicinal agent fortherapeutic purposes, e.g. for treating drug addiction and drugdependence (DE-A 199 06 978), for the therapy of Alzheimer's dementia(DE-A 199 06 975), or for the therapy of nicotine dependence (DE-A 19906 979).

Compound (I), known under the designation of pegen-(9)-one-(8), is animportant intermediate product in the synthesis of deoxypeganine andother chinazoline alkaloids of this type. The synthesis ofpegen-(9)-one-(8) (short: pegenone) can be performed according to SPÄTHand PLATZER (Ber. 68 (1935), 2221-2224) by converting isatoic acidanhydride with an equimolar amount of pyrrolidone. Subsequently, ahigh-vacuum distillation at 140 to 160° C. must be carried through inorder to separate the reaction byproducts. This method is suitable onlyfor small amounts (in the gram range), but not for production on alarger scale.

According to MORRIS, HANFORD and ADAMS (J. Amer. Chem. Soc. 57 (1935),951-954), pegenone (2,3-trimethylene-4-chinazolone) can be obtained (i)by oxidation of deoxyvasicine by means of hydrogen peroxide.Deoxyvasicine is identical with deoxypeganine. Alternatively, (ii),pegenone can be obtained by multistage synthesis, with γ-phenoxybutyrylchloride being reacted with o-aminobenzamide to the corresponding amide.After ring closure under heating, the phenoxyl group is replaced bybromine, and subsequently, through a further ring closure,2,3-trimethylene-4-chinazolone (=pegenone) is obtained.

If pegenone is required as a starting compound for the production ofdeoxypeganine, the only method that could be taken intoconsideration—apart from the method according to SPÄTH and PLATZERmentioned above—is, if at all, the synthesis method (ii) proposed byMorris et al. This method, however, is uneconomical due to the number ofreaction steps.

Deoxypeganine is preferably obtained by isolation from Syrian rue(Peganum harmala), or by synthesis.

MORRIS, HANFORD and ADAMS (loc cit., p. 953) describe the production ofdeoxyvasicine (=deoxypeganine) by reduction of2,3-α-hydroxytrimethylene)-4-chinazolone or2,3-(α-chlorotrimethylene)-4-chinazolone, using glacial acetic acid andzinc dust (reaction type: Clemmensen reduction). Following chloroformextraction, the product was isolated by crystallisation from petroleumether. It is disadvantageous here that the starting compounds(2,3-(α-hydroxytrimethylene)-4-chinazolone or2,3-(α-chlorotrimethylene)-4-chinazolone) have to be synthesizedstarting from peganine (=vasicine).

According to SARGAZAKOV et al. (Khim. Prir. Soedin. 4 (1990), 506-507),deoxypeganine hydrochloride can be obtained by cyclocondensation ofanthranilic acid with 2-pyrrolidone to give deoxyvasicinonehydrochloride (=pegenone hydrochloride) and subsequent Clemmensenreduction of this intermediate product to give deoxypeganinehydrochloride. The cyclocondensation reaction is performed in thepresence of phosphorus trichloride, with toluene being used as solvent.Both after the first step (cyclocondensation) and after the second step(reduction), multiple chloroform extractions are necessary. Altogether,the production of 2 kg of deoxypeganine hydrochloride requires approx.50 l of toluene and 80 l of chloroform.

The synthesis method described by SARGAZAKOV et al. is disadvantageousfor several reasons. The yield amounts to only approx. 50%, the productobtained (deoxypeganine hydrochloride) being of a purity of 94-95%. Thismethod requires large amounts of organic solvents, especially tolueneand chloroform, as well as phosphorus trichloride. This isdisadvantageous for reasons of ecology, but also for reasons of safetyand cost. In addition, this method requires great expenditure of timeand work since several chloroform extraction steps have to be carriedthrough in order to achieve the aforementioned degree of purity. With aview to the use of deoxypeganine as medicinal agent it is especiallydisadvantageous that chlorohydrocarbons are used.

In the above-mentioned known synthesis methods, it is furthermoredisadvantageous that due to the high proportion of reaction byproducts,isolation of the products by crystallisation methods is not possible andcan instead be attained only by costly extraction steps or high-vacuumdistillation.

SUMMARY OF THE INVENTION

It was therefore an object of the present invention to indicatesynthesizing processes for the production of chinazoline alkaloids ofthe above-indicated formulas (I) and (III) which

enable yields and degrees of product purity which at least correspond tothose of known processes, or which surpass them;

enable the production of deoxypeganine (III) for use in the manufactureof medicaments;

largely do without the use of substances which are damaging to theenvironment or to health, especially organic solvents;

have a good raw material balance;

substantially produce only such byproducts as can be readily recycled;

can be carried through using cost-effective starting materials; and

altogether enable a simpler and more cost-effective production of theabove mentioned compounds on an industrial scale.

These and other objects are surprisingly achieved by methods accordingto the independent claims 1, 9, 18 and 20, as well as by the furtherembodiments described in the dependent claims.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

According to claim 1, in a process according to the invention, acompound of formula (II) (=isatoic acid anhydride)

is reacted with 2-pyrrolidone (=pyrrolidinone) to obtain a compound offormula (I). In this reaction, an excess of 2-pyrrolidone is used,relative to the amount of compound (II) used. This means that the amountof pyrrolidone used is larger than the equimolar amount. For example,1.5 to 5 mol, especially 2 to 4 mol, or even 2.5 to 3.5 mol, ofpyrrolidone are used, each of these values relating to the amount ofcompound (II) used.

This surprisingly has as a consequence that the formation ofunfavourable reaction products is reduced and that the nascent product(I) can be readily crystallized. In addition, it is possible to obtainhigh yields (70%), with purity at approximately 99% (NMR). Due to theexcellent crystallizability, it is possible to dispense with expensivepurification methods, such as high-vacuum distillation.

Since purification of the product can be achieved in a simple manner bycrystallization, the process can also be carried through on a largerscale without any problems.

The process is based on the following reaction equation, presented byway of example:

The reaction is performed under addition of heat, such as attemperatures in the range of 50 to 200° C. The initial temperature maybe in the range of 70 to 130° C., and subsequently a temperature in therange of 140 to 200° C. is maintained; for example, the temperature isinitially 80 to 120° C., and later is 150 to 190° C.

The aforementioned initial temperature may be maintained for a period of0.5 to 2 hours, especially 1 to 1.5 hours, after the start of thereaction. The aforementioned subsequent temperature is maintained for aperiod of 1 to 8 hours, especially 2 to 5 hours.

The process is carried through by providing pyrrolidone and thereafteradding thereto the compound (II) in portions.

It is particularly advantageous to isolate product (I) directly from thereaction mixture by crystallisation. To crystallize compound (I), thereaction mixture is left to cool and is seeded with seed crystals.Crystallization is carried through at room temperature, such as at least25° C., with preference 30 to 70° C., or even 40 to 60° C., whereby thecourse of the crystallization is accelerated. The crystallizationprocess takes approximately 24 hours to 7 days, preferably approximately50 hours to 100 hours. The resultant crystals contain pyrrolidone.

The present invention further relates to processes for the production ofdeoxypeganine (compound according to formula III). The processessubstantially comprise three steps:

Producing compound (1) according to a process according to the presentinvention;

-   -   a reduction reaction, giving compound (III) in salt form; and    -   liberating compound (III) from the salt.

The course of the reduction reaction (Clemmensen reaction) can beindicated, by way of example, as follows:

Compound (III) is here obtained in the form of a salt; in the casepresented above by way of example, tetrachlorozincate salt is obtainedif the reduction reaction is carried through in the presence of glacialacetic acid, zinc, and hydrochloric acid.

Particularly, the starting compound (I) used is a reaction productisolated by crystallisation and this reaction product can be obtained bythe above-described processes.

According to one embodiment of the invention, the reduction reaction isperformed using glacial acetic acid, zinc (zinc dust) and hydrochloricacid, which is done by initially dissolving compound (I) in glacialacetic acid and subsequently adding zinc and hydrochloric acid.

According to an alternative embodiment of the present invention, thereduction reaction is performed under addition of zinc (as zinc dust)and sulfuric acid, without use of glacial acetic acid. This yields thehydrogen sulfate of compound (III):

The reaction is carried through at temperatures of approximately 50 to90° C., especially 70 to 80° C.; generally, the reaction hasquantitatively terminated after about 2 to 3 hours. After termination ofthe reaction, the excess zinc is removed by known methods, e.g. bycolation.

The salt of compound (III) thus obtained can be isolated in a simple andefficient manner by crystallisation from the reaction mixture. For thispurpose, the reaction mixture is seeded with seed crystals. When thecrystallisation has taken place, the remaining mother liquor isseparated by methods known to those skilled in the art (e.g. decanting).

In the above-mentioned step (C) of the inventive processes for theproduction of a compound of formula (III), the salt obtained in step (B)is then converted to the free base (III).

This is generally done by adding a base, preferably NaOH, to an aqueoussolution of the salt.

According to one embodiment of the present invention, this step iscarried out in such a manner that the liberated base is obtained inmolten form. This is achieved by carrying through the reaction at atemperature that is higher than the melting point (86° C.) of the freebase (III) (=deoxypeganine) at temperatures in the range of from 90 to100° C. The base present in molten form can be separated in a simplemanner, possibly after freezing, from the reaction mixture. Methodssuitable for this purpose are known to those skilled in the art.

According to a further embodiment, the molten base (III) is thereaftercooled down and left to freeze. The frozen product is dissolved toobtain a saturated solution and water is used as the solvent. From thissaturated solution, which is adjusted so as to be alkaline by additionof a base (such as NaOH), the final product deoxypeganine can beisolated in high-purity form through the subsequent crystallisationprocess.

The invention thus extends to processes for the production ofdeoxypeganine (compound of formula (III)) which contain a step whereinthe compound is separated from the reaction mixture in liquid form. Moreparticularly, the invention encompasses production processes of the kindmentioned which contain the following process steps:

reducing the mentioned compound (I) to compound (III), whereby compound(III) is formed in salt form;

adding of a base, whereby compound (III) is liberated from the salt andseparates out in liquid form.

The inventive processes enable a simple and economical manufacture ofthe mentioned compounds (I, III) in a quantity and purity required inthe production of medicaments. It is particularly advantageous here thatthe use of organic solvents can be dispensed with.

The processes according to the invention will in the following beillustrated by examples.

EXAMPLE 1 (COMPARISON EXAMPLE)

Preparation of pegen-9-(one)-(8) (identical with formula (I)) byconverting pyrrolidone with an equimolar amount of isatoic acidanhydride according to SPÄTH and PLATZER (loc cit., p. 2221) and 2224.

Two litres liters of pyrrolidone were heated with 4 kg of isatoic acidanhydride (molar quantity ratio 1:1.07), in a chrome steel vessel(receptivity: 10 l), under vigorous stirring, to 120° C. until incipientgas formation. This was followed by heating for 10 minutes to 160° C.and subsequently for 30 minutes to 190° C. Of this reaction mixture, 558g (=3 mol) was transferred, in still hot-liquid state, into a 1-literflask (NS 29). The residue remaining in the steel vessel froze to ablack, glassy mass which is not suitable for isolation of pegenone.

From the reaction mixture (558 g) transferred into the flask, up to 117g of pegenone could be distilled by high-vacuum distillation using adistillation condenser that was heated to 120° C. This corresponds to ayield of 21%. After recrystallization from ether, a melting point of111° C. was determined.

EXAMPLE 2 Synthesis of Pegenone (Compound According to Formula (I))

One mole of isatoic acid anhydride (formula (II)) was converted with 3mol of pyrrolidone. To this end, pyrrolidone was placed in a heatablechrome steel drum (30 liters) and heated to approximately 100° C.,subsequently isatoic acid anhydride was added in portions while stirringcontinuously.

After approximately 1 hour, the entire amount of isatoic acid anhydridewas dissolved in pyrrolidone. This was followed by heating for 5 hoursup to 155 to 160° C. (during this process, CO₂ and H₂O was formed; seeabove) and finally by heating for a short time up to 170 to 180° C.

After cooling to approximately 50° C., the mass thus obtained was seededwith pegenone crystals and left to crystallise for approximately 50 to100 hours at room temperature. By increasing the temperature (at least25° C.), the crystallisation process could be accelerated (duration onlyapproximately 2 to 3 days). The “mother liquor” was separated from thecrystals by decanting.

Altogether, more than 90% of the starting compounds used were convertedto pegenone. The yield of crystallised pegenone was 40%; the remainingportion of the pegenone is dissolved in pyrrolidone. The pegenonecrystals obtained still have a content of 30%-mol of pyrrolidone,according to NMR; the purity of the pegenone is approximately 99%according to NMR.

In a modification of this process, the starting compounds were used in aquantity ratio of 1:2.5 (isatoic acid anhydride:pyrrolidone). Theproportion of the crystallised pegenone could thereby be increased toapproximately 55%, at a purity of approximately 99%.

EXAMPLE 3 Clemmensen Reduction of Compound (I)

The pegenone crystals prepared according to Example 2 (2.5 kg) with acontent of 15%-wt of pyrrolidone. This corresponds to 1.83 kg or 9.81mol of pure pegenone) were dissolved at approximately 50° C. in 6.1 l(=100.4 mol) of glacial acetic acid and transferred into a chrome steelvessel (50 liters). Subsequently, 3.7 kg (=56.4 mol) of zinc dust wasadded in small portions, during which process the temperature of thereaction mixture was kept at approximately 60° C. After approximately 1hour, 4×3 liter of concentrated HCl (32%; corresponding to 121.74 mol)were added, in small portions, within 2 hours while stirringcontinuously. Thereafter (after approximately 4 to 5 hours) the excesszinc dust was removed from the reaction mixture by colation. Afterseeding with seed crystals, approximately 66% of the deoxypeganine saltcould be separated by crystallization. The remaining mother liquor wasnarrowed down by evaporation, whereupon 66% of the deoxypeganine saltagain crystallized. Altogether, approximately 90% of the deoxypeganinesalt could be obtained in crystalline form.

b) Liberation of Deoxypeganine Base (Compound (III))

Crystals (2.5 kg) obtained in this manner were dissolved in hot water(approximately 1 l liters). Subsequently, NaOH was added under stirring(approximately 8 kg rotulae), while heating the mixture to 95 to 100° C.This yielded deoxypeganine in molten form, and this was separated fromthe reaction mixture. After freezing, the product was again dissolved inheated water to obtain a saturated solution, which solution was adjustedwith NaOH so as to be alkaline. From this saturated alkaline solution,deoxypeganine was isolated by crystallisation.

The deoxypeganine yield, relative to the deoxypeganine salt, was morethan 90%, with a purity of 99.9% (NMR).

EXAMPLE 4 Clemmensen Reduction of Compound (I) (Alternative Method)

175 g pegenone crystals (containing 30%-mol of pyrrolidone; thiscorresponds to 150 g of pegenone; see Example 2) were mixed with 750 mlof (20%) H₂SO₄ and heated (approximately 85° C.) for approximately 30min while stirring.

Subsequently, 260 g of zinc dust was gradually added (duration:approximately 2 hours). After approximately 1 hour, H₂SO₄ was addedagain (375 ml, 40%). After a total of approximately 3 hours, thereaction had terminated, and the excess zinc was separated by colation.

As described under Example 3 a), the deoxypeganine salt obtained wasseparated from the reaction mixture by crystallisation. The liberationof the base was carried through according to the method described underExample 3 b).

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible. Accordingly, the present invention is intendedto embrace all such alterations, combinations, modifications, andvariations that fall within the spirit and scope of the appended claims.

1. A process for producing a compound or reaction product of thefollowing formula (I)

comprising the steps of converting a compound of formula (II) with2-pyrrolidone, wherein 2-pyrrolidone is used in excess relative to saidcompound (II) to form a reaction mixture.
 2. The process according toclaim 1, further comprising the step of crystallizing said reactionproduct (I) to isolate said reaction product (I) directly from saidreaction mixture.
 3. The process according to claim 1, wherein saidprocess comprises using 2-pyrrolidone in an amount of 1.5 to 5 molrelative to the amount of compound (II).
 4. The process according toclaim 1, wherein said process comprises performing said conversion at atemperature of 50 to 200° C.
 5. The process according to claim 4,wherein said process comprises the step of initially heating saidreaction mixture to an initial temperature of 70 to 130° C. andsubsequently heating said reaction mixture to a subsequent temperatureof 140 to 200° C.
 6. The process according to claim 5, wherein saidprocess comprises the step of maintaining said initial temperature for aperiod of 0.5 to 2 hours and maintaining said subsequent temperature fora period of 1 to 8 hours.
 7. The process according to claim 6, furthercomprising the steps of: cooling said reaction mixture; seeding saidreaction mixture, after cooling with seed crystals of compound (I); andmaintaining said reaction mixture seeded with said seed crystals at roomtemperature, for a period of 24 hours to 7 days to enablecrystallisation.
 8. The process according to claim 7, wherein saidcrystallisation is carried through at a temperature of 30 to 70° C.
 9. Aprocess for the production of a compound of the following formula (III),comprising the following steps:

(A) Preparing said compound (I) according to a process according claim1; (B) performing a reduction reaction to provide said compound (III) insalt form; and (C) liberating compound (III) from the salt.
 10. Theprocess according to claim 9, wherein said process comprises using areaction product isolated by crystallisation according to claim 1 ascompound (I).
 11. The process according to claim 9, comprising the stepof performing said reduction reaction (step B) in the presence of zincand acid.
 12. The process according to claim 11, comprising the step ofinitially dissolving said compound (I) in glacial acetic acid andsubsequently adding zinc and hydrochloric acid to said compound (I)dissolved in glacial acetic acid.
 13. The process according to claim 12,comprising the step of performing said reduction reaction in thepresence of aqueous sulfuric acid and zinc dust.
 14. The processaccording to claim 9, further comprising the step of, subsequent to step(B), isolating said compound (III) as a salt by crystallisation fromsaid reaction mixture.
 15. The process according to claim 9, furthercomprising the step of, in step (C), adding a base to said reactionmixture to liberate said compound (III) from the salt.
 16. The processaccording to claim 15, wherein step (C) is carried through underheating, and further comprising the step of obtaining said compound(III), which is liberated from the salt, in molten form.
 17. The processaccording to claim 16, further comprising the step of cooling down saidcompound (III) present in molten form by freezing and, after freezing,crystallizing said compound (III) from an aqueous alkaline solution. 18.A process for the production of a compound (III), starting from a saltof said compound (III), comprising the step of liberating and isolatingsaid compound (III) from the salt as a free base in molten form.
 19. Theprocess according to claim 18, further comprising the step of coolingdown said compound (III) present in molten form to freezing subsequentlycrystallizing said compound (III) from an aqueous alkaline solution. 20.The process for the production of a compound of formula (III) accordingto claim 18, further comprising the step of separating said compound(III) from the reaction mixture in liquid form.
 21. The process for theproduction of a compound of formula (III), according to claim 20,further comprising the following steps: reducing said compound (I) tocompound (III) to provide said compound (III) in salt form; and adding abase to said compound (III) to liberate said compound (III) from thesalt and to separate said compound (III) out in liquid form.
 22. Use ofa compound of formula (I), produced according to a process according toclaim 1, for producing a compound of formula (III) in a form selectedfrom the group consisting of a free base and a salt.
 23. The processaccording to claim 3, wherein said process comprises using 2-pyrrolidonein an amount of 2 to 4 mol relative to the amount of compound (II). 24.The process according to claim 23, wherein said process comprises using2-pyrrolidone in an amount of 2.5 to 3.5 mol relative to the amount ofcompound (II).
 25. The process according to claim 5, wherein saidprocess comprises the step of initially heating said reaction mixture toan initial temperature of 80 to 120° C. and subsequently heating saidreaction mixture to a subsequent temperature of 150 to 190° C.
 26. Theprocess according to claim 6, wherein said process comprises the step ofmaintaining said initial temperature for a period of 1 to 1.5 hours andmaintaining said subsequent temperature for a period of 2 to 5 hours.27. The process according to claim 7, comprising the step of maintainingsaid reaction mixture seeded with said seed crystals at a temperature ofat least 25° C. for a period of 50 to 100 hours to enablecrystallisation.
 28. The process according to claim 8, wherein saidcrystallisation is carried through at a temperature of 40 to 60° C. 29.The process according to claim 15, wherein said base is NaOH.
 30. Use ofa compound of formula (I), produced according to a process according toclaim 9, for producing a compound of formula (III) in a form selectedfrom the group consisting of a free base and a salt.